Method and system for adding sensory conditioning cues in a pharmacotherapeutic regimen

ABSTRACT

A method and system for administering pharmaceutical agents to a subject is provided. The system includes a course of treatment regimen, which includes a prescribed order of medicine amounts for periodic administration to the subject in the prescribed order. The amount of medicine includes a dose of at least one active pharmacological agent (APA) and an amount of at least one non-active pharmacological agent (NPA). The NPA provides at least one non-visual sensory cue. The dosage amounts of the APA contained within the amounts of medicine periodically administered in the prescribed order are varied within the course of treatment regimen, and the amount of the NPA contained within the amounts of medicine periodically administered in the prescribed order are held constant within the course of treatment regimen.

This application is a continuation of U.S. patent application Ser. No.13/691,131 filed Nov. 30, 2012, which claims priority to U.S.Provisional Patent Application Ser. No. 61/566,386 filed Dec. 2, 2011and U.S. Provisional Patent Application Ser. No. 61/566,915 filed Dec.5, 2011.

BACKGROUND OF THE INVENTION 1. Technical Field

The present invention describes a method for administering activepharmaceuticals (chemically synthesized, bioengineered, naturallyoccurring, or botanically derived) to a patient during a course oftreatment. In particular, the present method makes use of the ‘placeboresponse’, and enhances it through the conditioning achieved bycombining initial therapeutic pharmacological levels of the activepharmaceutical agent with “inactive” conditioning agents that contain asensory cue or cues. The term “inactive” means that the agent is notknown to have significant pharmacological effects or only minor effectsunrelated to the effects of the APA. The term “sensory conditioning cue”refers to both conscious conditioning and/or subconscious conditioning.

BACKGROUND INFORMATION

It has been shown in numerous studies that when patients believe theyare receiving a potent medication (even though the “potent” medicationcontained no active pharmacological ingredients) they will heal morerapidly and/or feel better more quickly and/or more fully than patientswho are not given such treatment. The administration of a “placebo”(i.e., a non-active substitute for an active pharmacological agent) canactivate physiological responses similar to those experienced by apatient receiving an active pharmacological agent. While the “placeboresponse” may not be entirely understood by modern science, it is welldocumented that rather than simply convincing patients into believingthat they are getting better, improving, or healed, the so-called“placebo” can actually effect a scientifically documentable improvementor cure. In many studies of pharmacological efficacy the “active drug”performs only marginally better or moderately better, and in some casesno better, or worse than the placebo. Physicians must often weighwhether this small additional level of improvement is worth theconcurrent risk of side effects caused by active pharmaceuticals.Placebos, by definition have little or no side effects since they arecomposed of substances generally recognized as safe and inactive. Theuse of placebos is widespread in both traditional and modern medicineand arguably form the foundation of many systems of medicine practicedaround the world.

The use of non-pharmacologically active (NPA) substances to effect acure is highly desirable for a variety of reasons, including the factthat NPAs typically: 1) have less or no side effects; 2) cost less; 3)have less or no interaction with other medications; 4) have a decreasedchance of addiction; and 5) have less or no side effects and/orcomplications associated with usage over an indefinite time period.

There are, however, a number of difficulties presented to a doctorwishing to treat a patient with a placebo. For example, a patient whoenrolls in a double-blind study will be informed that they may be givena placebo treatment as part of their participation in the study. Absentthis informed consent of the possibility of taking placebos, there arepotentially serious ethical dilemmas associated with a doctor telling apatient he is receiving an active pharmacological agent (APA) when he isin fact being given a placebo. This can prevent a doctor from giving apatient a placebo, thereby limiting or attenuating the potential benefitof the placebo response to the patient's health.

SUMMARY OF THE INVENTION

The current invention provides a method and system for administering anamount of medicine containing an active pharmaceutical agent and aplacebo-response-evoking agent consisting of a NPA that gives a sensorycue combined in a unitary dose form with the APA. The efficacy of theNPA as an evoker of the placebo response is augmented by coupling thesensory cue containing NPA with the active pharmacologic agent, and byadministering in a form that has detectable sensory effects (e.g.,taste, smell, sound such as verbal communication, cutaneous sensation,oropharyngeal or esophageal/gastric somatosensory, or sensations such aswarmth or coolness, etc.) thereby causing the patient consciously and/orunconsciously to associate the sensory cue with the effects of the APA.The NPA may be substances that are generally recognized as safe or GRASagents, but any agent that is not a cause of serious untoward effectsmay be employed. This association, conditioning, or learning will allowthe sensory cue to evoke effects similar to the APA via what is referredto as the ‘placebo response’ thereby permitting lower amounts of APA tobe used in subsequent doses when accompanied by theplacebo-response-evoking sensory cue contained in the NPA. Sensory cuesthat may be employed in this invention include those mentioned as wellas cues derived from somatic senses including the sensations of touch,pressure, temperature, nociception (pain) and proprioception.Oropharyngeal somatosensory sensations are somatic sensations perceivedin the oropharynx, the region extending from the uvula to the hyoidbone.

According to an aspect of the present invention, a method foradministering pharmaceutical agents to a subject is provided. The methodincludes the steps of: a) providing a course of treatment for a subject,which course includes periodically administering an amount of medicineto the subject, which amount of medicine includes a dose of at least oneactive pharmacological agent (APA) and an amount of at least onenon-active pharmacological agent (NPA), which NPA provides at least onenon-visual sensory cue; and b) varying the dosage amount of the APAwithin the periodically administered amount of medicine (e.g., generallyperiodically decreasing the APA from customarily prescribed dosages todosages below the generally prescribed dosage of the APA), while theamount of the NPA contained within each periodically administered amountof medicine is provided at a constant level that maintains the sensorycue at a substantially consistent level from dose to dose.

According to another aspect of the present invention, a system foradministering pharmaceutical agents to a subject is provided. The systemincludes a course of treatment regimen, which includes a prescribedorder of medicine amounts for periodic administration to the subject inthe prescribed order. The amount of medicine includes a dose of at leastone active pharmacological agent (APA) and an amount of at least onenon-active pharmacological agent (NPA). The NPA provides at least onenon-visual sensory cue. The dosage amounts of the APA contained withinthe amounts of medicine periodically administered in the prescribedorder are varied within the course of treatment regimen, and the amountof the NPA contained within the amounts of medicine periodicallyadministered in the prescribed order are held constant within the courseof treatment regimen.

For many of the sensory cues that can be used under the presentinvention, the sensation provided by that sensory cue is preferably, butnot necessarily, initially perceived by the subject about the same timeas the onset of the pharmacological effect (from the APA) is noted bythe subject. Most preferably, the perception of the sensory cuetemporally overlaps with the pharmacological effect of the APA. The term“about the same time” is used herein to mean that the two events (i.e.,the perception of the sensory cue and the onset of the pharmacologicaleffect) occur at the same time, or alternatively in temporal proximitythat is close enough such that the two events can be causally linked bythe subject. In some instances, a greater period of time between theperception of the sensory cue and the onset of the pharmacologicaleffect is acceptable; e.g., a sensory cue that occurs sometime before orafter the onset of the pharmacological effect has taken place.

For example, the onset of analgesia with narcotics may be some period oftime (e.g., fifteen minutes to forty-five minutes) after the drug istaken. Factors that can affect the onset of the drug include the drugitself, the method of administration of the drug (e.g., oral,sublingual, transmucosal, intravenous intramuscular, subcutaneous ortransdermal), or the formulation of the drug; e.g., a rapid dissolutionformulation, or a formulation that delays onset, such as an entericcoated drug, or a continuous release formulation. Depending upon theknown pharmacokinetics of the APA and its method of administration, thesensory cue is preferably formulated to effect its perception at orabout the same time as the APA begins to be effective. As anotherexample, consider an oral narcotic agent whose expected onset of actionis about thirty minutes. The sensory cue (e.g., a taste and olfactorysensation such as cinnamon) could be provided with the narcotic agent insuch a manner that it is ingested at the same time as the narcoticagent, but is not perceived by the subject until the onset of thenarcotic agent. Aromatic volatile oils such as mint, ginger, eucalyptus,thyme, aniseed, garlic, and wintergreen are other examples of sensorycues that could be used in such a “timed” application. As yet anotherexample, the sensory cue NPA may be contained on the exterior of a pillor capsule or in the interior core of a pill/capsule beneath atime-release delay coating so that the coating dissolves and releasesthe NPA at about the same time the APA is perceived as acting. As aresult, the subject feels a sensation of warmth, coolness, or tinglingin their upper digestive tract, or smells the absorbed aromatic volatileoil on their breath either by its presence in their blood andtransmission to their expired air, or through eructation of gastric gasto the pharynx close to the time that the patient feels the effects ofthe APA. Any NPA having a perceived sensation may be employed.Cutaneously administered drugs, or rectal or vaginal suppositories, mayinclude a warming, cooling, slight burning or tingling agent as the NPAsensory cue incorporated into the cutaneous mechanism (e.g., a patch)containing the APA, formulated so that their perception occurs about thesame time as the onset of the APA's physiologic response.

The duration of the sensory cue can vary to suit the application. Inmany instances the causal relationship between the sensory cue and thepharmacological effect of the APA is enhanced by extending the durationof the sensory cue. Typically, the duration of the sensory cue isseveral seconds to several minutes, although in some instances thesensory cue may be perceivable by the subject for the entire time theAPA has a pharmacological effect. The specific duration can be tailoredto suit the application at hand.

The term “constant” is used herein to describe, for example, that theamount of an NPA contained within each periodically administered amountof medicine is provided at a level that maintains the perception of thesensory cue(s) at a substantially consistent level and is constant fromdose to dose, while the APA dose is varied and generally decreased. Inthat context, the term “constant” is used to mean that the amount of theNPA contained within the administered amounts of medicine, and thereforethe associated sensory cue, is substantially the same within each of theadministered amounts; e.g., each administered amount of medicine has thesame amount of NPA in it, and consequently the perceived sensation fromthe sensory cue is the same in each administered amount of medicineregardless of the dosage of APA within the amount of medicine. In thiscontext, the term “constant” does not mean that the perceivable aspectof the sensory cue (e.g., its intensity) necessarily remains the sameall the time the medicine is administered. As indicated above, thesensory cue typically, but not necessarily, has a duration that is lessthan the pharmacological duration of the APA. For example, the APA mayhave a pharmacological duration that lasts a period of four hours, butthe sensory cue may only last ten minutes. In those preferredapplications where the onset of the pharmacological effect begins at thesame time as the onset of the sensory cue and using the details of thisexample, the sensory cue is perceivable by the subject during the firstten minutes of the four hour APA duration period.

In some applications, it is possible that a course of treatment thatincluded a relatively low dosage of APA over an extended period of timecould result in an attenuation of the desired response from the subject;e.g., the desired association of the sensory cue to the perceivedpharmacological effect of the APA can be diminished—a process sometimesreferred to as “extinction”. In such an event, or to prevent such anevent, the present method and system can include a periodic amount ofmedicine that includes a greater dose of the APA than the earlierapplied doses (e.g., a “spike” in APA dosage) which is followed by theresumption of the lower dose of the APA with the standard sensory cue;i.e., the resumption of the normal regimen. This aspect of the presentmethod and system would help to prolong the efficacy of the APA in lowerdose amounts and would also be advantageous to the patient in that itwould more rapidly restore the conditioned physiologic response due tothe “relearning” of the conditioned response initial learned under thesystem. This aspect of the present invention may be referred to as“intermittent reinforcement”. It can be accomplished by giving a singledose of a higher APA with the sensory cue followed by resumption of thepreviously administered lower dose or the lowest effective dose.

In some embodiments, the physician may continue to administer thecombination of the NPA and APA, with the APA at the lowest effectivelevel for the patient and the NPA at a constant original level, therebyminimizing side effects of the APA that may be dose dependent. The APAdose level may be at any level within the generally recommended doselevels to levels that are thought to be pharmacologically inactive; theAPA may be administered at a dosage that is the lowest dosage that willbe effective for the patient taking the combined APA and NPA of thepresent invention.

One of the advantages provided by the present method is that the sensorycue(s), of perceived taste (such as that of cinnamon or chocolate), ortingling (such as that induced by Echinacea), or sense of heat/minorburning sensation (such as that induced by capsaicin or ginger), orsense of cooling (such as that induced by menthol) associated with theAPA is stronger and longer lasting and much more certain to be perceivedthan a visual cue. It is known in the prior art to use a placebo dose ofmedicine within a prescribed course of treatment. For example, U.S. Pat.No. 6,855,324 “Therapeutic Placebo Enhancement of Commonly-UsedMedications” describes a method for reducing the normal dosage of apharmaceutical that involves the use of visual indicia associated theuse of a full dosage and with a placebo (e.g., “the pill marked ‘XXX’ isthe strong one”). At a certain point in the treatment, a reduced dosageof the pharmaceutical is used with the placebo. Problems with using avisual indicia include the fact that they are only discernible prior tobeing ingested, they require the subject to be able to see them, andonce ingested they are gone—nothing remains to reinforce the associationbetween the visual cue and the medicine with which it is associated.Equally problematic is the fact that many medications are taken togetherand or administered to the patient by others and visual cues aretherefore non-effective. The present invention, in contrast, uses asensory cue that can remain with the subject for a period of time, doesnot rely on the subject's ability to see, and will be substantially morenoticeable that a visual cue; e.g., a bitter flavor or tinglingsensation can stay in the subject's mouth for a sufficient period oftime to reinforce the desired association with the APA.

Another advantage of the present invention is that the present methodfor administering an amount of medicine capitalizes on and potentiallyincreases the reassurance provided to a patient by his or her physician.The present coupling of a placebo with an active pharmacologic agent,which coupling generally requires a prescription or contact with his orher healthcare provider and therefore requires enhanced contact betweenthe physician and patient, further augments the placebo responseexperienced by the patient. Coupling the placebo and the APA also avoidsdisclosure difficulties associated with a doctor wishing to treat apatient with a placebo. The co-administration of a placebo together withan APA resolves the disclosure difficulties since the patient will factbe receiving an APA. The combination described in the present inventionwill allow the physician to use the lowest possible dosage of APAthereby decreasing (or possibly eliminating) the dose related sideeffects of the APA, thereby enhancing the efficacy of the APA and or theefficacy of the placebo depending upon ones perspective. The net effectis that the patient will get the same therapeutic response from a lowerdose of APA thereby reducing (or possibly eliminating) untoward effects,or side effects, of the APA.

Subjects likely to benefit by the present method include those that aretaking an APA for pain, mood disorders, anxiety, high blood pressure,depression, asthma, allergies, drug dependence, addiction to nicotine,insomnia, as well as symptoms triggered by chemical sensitivities. Itwill also benefit many other conditions including those with a possiblepsychosomatic trigger such as irritable bowel syndrome, sexualdysfunction, eating disorders including obesity, back pain, and variousphobias.

The present apparatus and advantages associated therewith will becomemore readily apparent in view of the detailed description providedbelow.

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, a method and system for periodicallyadministering a medicine containing one or more active pharmaceuticalagents (chemically or biologically synthesized, or botanically derived)to a patient within a prescribed course of treatment is provided. Theperiodically administered medicine may assume a variety of differentforms (e.g., pill, capsule, tablet, powder, cream, patches, liquid, gas,etc), depending upon the application at hand. In some embodiments, themedicine may be in a form that contains a pharmaceutical agent in a formthat is otherwise available to the public, which form is modifiedaccording to the present invention; e.g., a commercially availablepharmaceutical pill, modified via coating or admixing to include anon-active pharmaceutical agent sensory cue. Hereinafter, the form ofthe medicine will be referred to hereinafter as a “pill” for ease ofdescription. The periodically administered medicine is not, however,limited to only a solid “pill” form.

The one or more active pharmacological agents (APAs) within the pill arespecifically chosen to create a desired effect on the subject taking themedicine. In addition to the APAs, each pill also includes an amount ofone or more non-active pharmacological agents (NPAs). The NPAs include acomposition that is, individually or collectively, capable of giving thepatient a conscious (perceptible) and/or unconscious (imperceptible) cueor cues (referred to hereinafter as a “sensory cue”) to its presence. Asensory cue may be perceptible immediately prior to or at the time ofingestion or application or within some period of time (e.g., thirty toforty-five minutes) after ingestion or application; e.g., cues such assmell, taste, tactile texture, mouth sensation, upper gastrointestinalsensation, and involuntary response (e.g., salivation). Sensory cuesinduced by stimulating the somatosensory system of the tongue and mouthinclude sensations such as burning, tingling, hotness, coolness,astringency, carbonation, mouthfulness (heartiness/kokumi), numbness,etc., can be particularly effective because of the response they create;e.g., one that can be stronger, longer lasting, and distinctive relativeto sensory cues that a patient is likely to normally encounter. Apatient having a dull sense of taste would likely readily recognize atingling sensation.

As indicated above, the medicine administered within the course oftreatment includes at least one NPA. In those embodiments including atleast two NPAs, the NPAs can, for example, be selected to include afirst NPA that provides a first sensory cue and a second NPA thatprovides a second sensory cue. The first sensory cue may be differentfrom the second sensory cue. In some instances, the first sensory cuemay be perceivable by the subject before the second sensory cue isperceivable by the subject. In other embodiments having at least twoNPAs, the NPAs may each provide the same or similar sensory cue. In someof these embodiments, the sensory cue of the first NPA may beperceivable by the subject before the sensory cue of the second NPA.

In some embodiments, the effectiveness of the present medication can beenhanced by application techniques. For example, if an NPA provides ataste, or a cool or warm oropharyngeal sensory cue (e.g., cues providedby peppermint, spearmint, wintergreen, or cinnamon oils, or theirsynthetic analog), the sensory cue can be enhanced by advising thesubject to not to eat or drink for a period of time (e.g., thirty tosixty minutes) after ingestion. The instruction to avoid eating ordrinking for the period of time will help prevent washing or dilutingthe NPA within the subject's pharynx and esophagus and consequently thesensory cue associated therewith. Alternatively, the subject may beinstructed to let the medication dissolve in their mouth withoutingestion of any liquids as in the case of sublingual administration ofthe medication.

The NPAs that create a sensory cue also create and/or reinforce (byconscious and/or subconscious mechanisms) an association between the cueand the effect associated with the APA. In some embodiments, theassociation between the cue and the APA effect is created when thesubject is treated with the medicine containing the APA over a period oftime, and the sensory cue accompanying the APA becomes associated withthe relief (i.e., effect) provided by the APA over the period of time.For example, under the present invention a pill containing a prescribeddosage of an anti-inflammatory agent could contain a specific amount ofan NPA that imparts an arbitrarily chosen flavor, a mouth sensation, orhas a distinct smell. After a period of time, that flavor, mouthsensation or smell will become associated with the anti-inflammatoryrelief provided by the APA. As a result, the subject will expect theanti-inflammatory relief, or be conditioned to experience the relief,when a pill is taken having the particular flavor, sensation, or smell.

In other embodiments, the association between the sensory cue and theAPA effect is a naturally occurring one (i.e., one that is independentof the medicine) that is reinforced when the subject is treated withmedicine containing the APA and a NPA that imparts a particular sensorycue. For example, a pill containing a prescribed dosage of a stronganti-inflammatory agent may contain a specific amount of an NPA thatcontains or mimics the flavor and mouth sensation of capsaicin (chilipepper), which flavor is associated with anti-inflammatory relief. Ifthe NPA actually contains capsaicin, the amount of the capsaicin is lessthan an amount that would provide anti-inflammatory relief to thesubject by itself, but is an amount that is sufficient to provide theflavor and sensation associated with capsaicin. Hence, theanti-inflammatory relief provided by the medicine is naturallyassociated with the taste and sensation of the capsaicin (chili pepper),but it is the APA that provides the anti-inflammatory relief—not thecapsaicin sensory cue associated with the aforesaid relief. Otherexamples of combinations of a product having a sensory cue that isassociated with particular relief and an APA that provides such reliefinclude, but are not limited to: a) licorice or peppermint associatedwith an APA that restores calm breathing; b) chamomile flavor associatedwith an APA that helps induce sleep or calms anxiety; c) ginger,peppermint, or fennel associated with an APA that helps dissipate orprevent motion sickness; d) peppermint or chamomile associated with anAPA that provides relief for irritated bowel syndrome; e) opiatealkaloids or opium-less and alkaloid-free seed poppy cultivar associatedwith an APA that provides pain relief; f) Echinacea alkymides and garlicassociated with an APA that is an antiviral; g) licorice or coffeeassociated with an APA that provides asthma relief; h) lemon balm,chocolate, or bitters associated with an APA that provides depressionrelief; i) bergamot associated with an APA that provides relief forobsessive compulsive disorder; and j) chamomile or licorice associatedwith an APA used to treat ulcers.

For medicines that are, or were originally, directly or indirectlybotanically derived, the NPA may contain non-active constituents of theplant from which it was derived. These non-active constituents, withnearly identical chemical compositions, may trigger unconsciousperceptions/cues and enhance the effect of the NPA treatment regimen.For example, in certain applications an APA such as caffeine may beadministered as treatment of various disorders and conditions (i.e.,migraines, fatigue). In such applications, decaffeinated coffee (i.e., anon-active constituent derived from a botanical source) can provide bothconscious and unconscious sensory cues that can enhance the effect ofthe NPA treatment regimen.

In some embodiments, a synthetically derived APA may be combined withone or more sensory cues of analogous plant medicines that produce thesame pharmacological actions. For example, a synthetic opioid may tastestrongly bitter and may numb the mouth like the Papaver somniferumalkaloid from which it was originally derived. A medication forflatulence or colic may have a fennel (Foeniculum vulgare) smell. Amedication for ulcerative conditions of the bowels may have a peppermintsmell which is known to have relaxing, anti-inflammatory effects on themuscles of the digestive system. A medicine to treat microbialinfections may include the alkylamides of Echinacea spp. that produce astrong tingling sensation on the tongue. The sensory cues (bothconscious and unconscious) assist the body in “understanding” andreacting to the medicine. They enhance the effect of the non-activepharmacological agents by providing memorable associative cues with themedication containing the active pharmacological agents.

Additional examples of sensory cues provided by an NPA include:diaphoretic/sudorific agents that increase the subject's propensity tosweat (e.g., elder flower, yarrow, cayenne/capsaicin); agents that coloror add odor to the subject's urine or feces (e.g., beet juice,asparagus); aromatic volatile oils that may be sweet, spicy, and/orfragrant (e.g., cinnamon, fennel, dill, lemon balm, peppermint,spearmint, ginger, caraway, eucalyptus, aniseed, thyme, sage, cardamom,wintergreen, juniper, chamomile, parsley, oregano, garlic); agents thatcause the subject's sweat to smell (e.g., garlic); sialagogue agentsthat increase the propensity of the subject to salivate (e.g., cayenne,ginger, gentian, black pepper); rubefacient agents that increaselocalized blood flow and warms the local area when applied to the skin(e.g., horseradish, mustard, cayenne, wintergreen, peppermint oil,rosemary oil, ginger); agents that provide a cool sensation (e.g.,refrigerant herbs such as aloe, hibiscus, orange, lemon, coriander,licorice); agents that provide a bitter taste/mouthfeel (e.g., gentian,horehound, yarrow, mugwort, wormwood, chamomile, dandelion); astringentagents that provide a taste/mouthfeel (e.g., tea, raspberry leaf, oak,yarrow); demulcent agents that provide a mouthfeel (e.g., oat, flax,marshmallow, licorice, slipper elm, cornsilk); agents that act as a mildstimulant (e.g., chocolate, cola, tea, coffee, rosemary, peppermint);and agents that provide a sour taste (e.g., lemon, citric acid). Theabove is a list of acceptable sensory cue agents. The present inventionis not limited to these examples, however. Other sensory cues not listedhere that cause any kind of noticeable but harmless bodily sensation maybe employed in the scope this invention.

In some embodiments, the NPA that creates or causes the sensory cue isadmixed with the APA within a particular form; e.g., a pill, liquid,gel, etc.

In other embodiments, the NPA that creates or causes the sensory cue isprovided in a form where it is not admixed with the APA. For example,the NPA could be a coating on materials that include the APA; e.g., acoating on a pill, etc. Alternatively, the NPA could be incorporatedinto, or coated onto a capsule that is used to contain materialsincluding the APA. For example, it is known to use gelatin capsules to“package” medicines, which “package” can be ingested. In many instances,but not all, the gelatin capsules are purposefully non-flavored. Inother instances, however, the capsules are purposely given a flavordesigned to increase the palatability of the capsule. U.S. Pat. No.6,346,231 “Flavored Gelatin Capsule and Method of Manufacture” disclosessuch a gelatin based capsule, and is incorporated by reference herein inits entirety. The flavor is chosen for solely for palatability purposes(e.g., to obscure unpalatable taste of fish oil), however, and there isno association with the relief provided by the APA. Under the presentmethod, the NPA can be incorporated into, or coated onto a capsule thatis then used to contain materials including the APA. One of theadvantages of this approach is that different medicines that produce thesame or very similar result, or variable dosages of one medication, canuse the same type of capsule having a particular sensory cue. Thepresent method is not limited to gelatin-type capsules, and can have anNPA included: 1) with the contents of the APA; 2) as a coating on an APApill surface; 3) at the core or inside of an APA pill and surrounded bya time-released coating; 4) within a second outer capsule containingboth the APA in its original form (e.g., pill) in addition to an NPA; 5)within the composition of the second capsule; or 6) as a surface coatingon the second outer capsule.

In those applications wherein the NPA is incorporated into, or coatedon, a capsule, that same capsule can be used to encapsulate a previouslymanufactured pill or capsule. In this manner, a sensory cued placebocould be readily used in a prescribed course of treatment as describedherein with any APA/medication. This application provides substantialutility because the placebo sensory cue can be added by different stagesin the production/administration of the medicine; e.g., added by theoriginal manufacturer of the medication, or by a second-party company topreviously manufactured medicine, or by a pharmacist filling aprescription with instructions to add a placebo cue—potentially within acourse of treatment wherein the dosage of the APA is reduced over time.

Under the present method, the amount of the APAs within eachperiodically administered pill is varied over a prescribed course oftreatment. In some embodiments, the amount of APA is decreased over aperiod of time. The present method is not limited, however, toembodiments wherein the amount of the APAs is decreased over time, andthe amount of APA may be otherwise varied as the signs or symptoms ofthe illness for which it is administered vary, and as the physician orhealth care provider direct. For example, in some embodiments where thedosage amount of the APA within each periodically administered amount ofmedicine is gradually decreased over the course of treatment, the APAdosage may be increased for a single dose to reinforce the conditioningprocess followed by resumption of the decreased dose of the APA; e.g.,if the course of treatment involves twenty amounts of medicine to beperiodically administered, and the dosage amount of the APA decreasesbetween the first application of the medicine and the tenth applicationof the medicine after which point the APA dosage plateaus at a decreasedamount, this embodiment of the present invention involves a “spike” inAPA dosage at some point during the “decreased amount plateau”. Thespike may be one or two APA applications at the initial dosage, followedby a return to applications of the decreased APA dosage amount.

Under the present method and system, the course of treatment regimen isoperable to be administered over a period of time, and that period oftime is long enough such that the subject will associate the sensory cueassociated with the NPA with the pharmacological actions of the APA,thereby inducing a conditioned response based on the sensory cue, whichresponse is similar to the APA.

The sensory cue provided (or caused by) the NPA in each pill enhancesthe action of the APA. As the amount of APA is gradually decreasedwithin each pill over time, the effect of the NPA induced placeboresponse proportionately increases and in some cases may become thepredominant healing factor. The present method is not limited to aparticular manner of decreasing the APA dosage; e.g., the decrease maysigmoidal with no or minimal taper for the first several days tomaximize conditioning followed by a exponential taper followed by aconstant or plateau low dose of APA, or be linear, with or without astep function, decrease, etc. As the amount of APA is decreased, thesensory cue provided by the NPA contained within each pill remainssubstantially constant and gives the subject the impression that eachpill is in fact the same. In most embodiments of the present method, theamount of the APA within each pill is decreased over time until a lowerlimit of APA is reached. At that point, each pill will contain the lowerlimit amount of APA so the subject is always taking some amount of APAduring the prescribed course of treatment. The decreased dosages of theAPA will very likely result in a significant decrease in APA associatedside effects, such as nausea, diarrhea, metabolic disorders, and others.

An additional means of associating the sensory cue with the actions ofthe APA is to employ a multi-layered, time-delayed release dose ofmedication wherein the sensory cue is released in temporal proximitywith the perceived action of the APA more than once in a givenadministered dose. This ‘teaching dose’ may be employed in topicalpatches, or in delayed release oral medications, or some combinationthereof. For example, the APA and the NPA within each periodicallyadministered medicine amount may be administered in a layeredarrangement having layers of NPA and APA so that sub-amounts of the NPAand APA within the medicine amount are sequentially released therebyenhancing the associative reinforcements. Additional methods, known tothose skilled in the technology, may include encapsulated granules ofNPA and APA so composed as to sequentially release at about the sametime in one episode or a series of episodes after the ingestion orapplication of a single dose. The layering of the NPA refers to bothphysical layering and/or temporal layering so that the release of theNPA and APA may be coordinated to best affect a conditioning associationbetween the sensory cue and the effects of the APA.

In the aforementioned manner, patients taking the prescribed medicinecan benefit from both the pharmacological action of the APA and theenhanced “placebo effect” of the NPA. The NPA placebo effect will beenhanced because it is associated (both consciously and unconsciously)with a true pharmacologic effect. The physician may prescribe amedication course of treatment wherein the amount of APA tapers down(e.g., “x” percent decrease per day) with no change in the number ofpills prescribed each day. Maintaining the prescription at a fixednumber of pills likely decreases the potential for medication dosingerrors; e.g., applications where the amount of APA is decreased bydecreasing the number of pills taken, leading to errors in the number ofpills to be taken. In many instances, the patient can continue to takethe medication containing the lowest dose of APA to which the disorderbeing treated is responsive. Maintaining the APA at a very low dose (butstill requiring a prescription) also provides the psychologicaladvantage of the subject being under a doctor's supervision and therebyenhancing the salutary effect of the doctor patient interaction andstrengthening the placebo response. The supervision helps reinforce theexpectation that the course of treatment is significant in providingrelief. In other embodiments, the amount of APA within each periodicallyadministered amount of medicine is below the lowest dose with a knownpharmacological effect, in which case the dosage of APA may beconsidered to be a non-active amount of the APA.

The present method for periodically administering a medicine containingone or more active pharmaceutical agents to a patient within aprescribed course of treatment utilizes packaging that facilitates theadministration of the medicine. For example, the medicine can bedispensed using a blister pack, or other sequence noting dispenser thatmakes clear the sequence of pills administered to date. This type ofpackaging is particularly useful for those applications wherein thepills containing the varying levels of APA and constant levels of NPAare visually identical or difficult to differentiate from each other.

Although the invention has been described and illustrated with respectto exemplary embodiments thereof, the foregoing and various otheradditions and omissions may be made therein and thereto withoutdeparting from the spirit and scope of the present invention.

What is claimed is:
 1. A pharmaceutical administration kit, comprising:a sequential order of medicine amounts, wherein each said medicineamount in the sequential order includes a dose of at least one activepharmacological agent (APA) and an amount of at least one non-activepharmacological agent (NPA), wherein the amount of NPA is configured toprovide at least one non-visual sensory cue; and wherein the APA dose ineach medicine amount within the sequential order is greater than thedose of APA contained within the next medicine amount within thesequential order, and each medicine amount in the sequential ordercontains substantially the same amount of the NPA, and wherein the APAdose in each medicine amount is a prescription drug; and packagingconfigured to hold the medicine amounts and indicate the sequentialorder of the medicine amounts.
 2. The kit of claim 1, wherein the atleast one APA is an opioid.
 3. The kit of claim 1, wherein the at leastone NPA is configured to provide a bitter taste as said non-visualsensory cue.
 4. The kit of claim 1, wherein the dose of APA isconfigured to produce a pharmacological effect, and the amount of NPA isconfigured to begin producing the at least one non-visual sensory cue atabout the same time as an onset of the pharmacological effect of theAPA.
 5. The kit of claim 4, wherein the NPA is configured in atime-release form.
 6. The kit of claim 1, wherein the dose of APA isconfigured to produce a pharmacological effect, and each medicine amountis configured to delay the amount of NPA producing the at least onenon-visual sensory cue until about the same time as an onset of thepharmacological effect of the APA.
 7. The kit of claim 6, wherein theNPA within each medicine amount is encapsulated with a coatingconfigured to dissolve a period of time after being ingested.
 8. The kitof claim 6, wherein each medicine amount is configured in a layeredarrangement with at least one layer of the dose of APA and at least onelayer of the amount of NPA, and the layered arrangement is configured tocause the dose of APA and the amount of NPA to be sequentially releasedafter being ingested.
 9. The kit of claim 1, wherein the at least onenon-visual sensory cue provided by the amount of said NPA is asomatosensory type sensory cue.
 10. The kit of claim 1, wherein thesequential order of medicine amounts includes a spike medicine amounthaving a spike APA dose, the spike APA dose being greater than the APAdose in the immediately previous medicine amount within the sequentialorder.
 11. The kit of claim 1, wherein the sequential order of medicineamounts includes at least two sequential medicine amounts having thesame APA dose.